Review Article 171

Sleep and Syndromes

Bernhard Schmitt1

1 Division of Clinical Neurophysiology and Epilepsy, University Address for correspondence Bernhard Schmitt, MD, Division of Children’s Hospital, Zurich, Switzerland Clinical Neurophysiology and Epilepsy, University Children’sHospital, Steinwiesstrasse 75, CH-8032, Zurich, Switzerland Neuropediatrics 2015;46:171–180. (e-mail: [email protected]).

Abstract Sleep and epilepsy have a close relationship. About 20% of patients suffer only during the night, approximately 40% only during the day and approximately 35% during the day and night. In certain , the occurrence of seizures is strongly related to sleep or awakening. Infantile spasms appear predominately on awakening, and is sometimes visible only in sleep. Children with or benign epilepsy with centrotemporal spikes (BECTS) have seizures mostly when asleep, and in both syndromes interictal spike waves are markedly accentuated in slow wave sleep. Electrical during slow sleep/continuous spike wave discharges during sleep (ESES/CSWS), atypical benign partial epilepsy, and Landau– Kleffner syndrome are epileptic encephalopathies with substantial behavioral and Keywords cognitive deficits, various seizures, and continuous spike–wave activity during non– ► sleep rapid eye movement (NREM) sleep. The hallmark of juvenile and ► epileptic grand mal seizures on awakening are symptoms within 2 hours after awakening, encephalopathy often provoked by sleep deprivation. Nocturnal is sometimes ► benign childhood mistaken for parasomnia. Differentiation is possible when the clinical symptoms and the focal frequency of the paroxysmal events per night and month are carefully observed and ► juvenile myoclonic nocturnal video (EEG) performed. Sleep EEG recordings may be epilepsy helpful in patients with suspected epilepsy and nonconclusive awake EEG. Depending on ► frontal lobe epilepsy the clinical question, sleep recordings should be performed during nap (natural sleep or ► parasomnias drug induced), during the night, or after sleep deprivation.

Introduction night. Furthermore, ISWs are often activated by sleep, which is why sleep electroencephalography (EEG) should Sleep and epilepsy have a reciprocal relationship. On one be considered when the wake EEG is not conclusive. hand, we have epilepsies with seizures occurring predomi- Distinguishing nocturnal seizures from nonepileptic nately during tiredness, during sleep or on awakening; on parasomnias can be challenging. A careful clinical history, the other hand, sleep quality, sleep architecture, and knowledge of key features of seizure syndromes and the restorative functions of sleep are compromised by parasomnias, and video-EEG monitoring are helpful seizures, interictal spike waves (ISWs), and antiepileptic to avoid misdiagnosis or redundant treatment with drugs (AEDs).1 William R. Gowers has shown, and other AEDs. authors have confirmed, that approximately 20% of patients This review provides a short overview of sleep-associated suffer seizures only at night, approximately 40% only epilepsy syndromes. Space limitations only allow the presen- during the day and approximately 35% during day and tation of the most essential aspects. For more details, readers

received Issue Theme Sleep and © 2015 Georg Thieme Verlag KG DOI http://dx.doi.org/ December 14, 2014 Neurodevelopmental Disorders; Guest Stuttgart · New York 10.1055/s-0035-1551574. accepted Editor, Oskar G. Jenni, MD ISSN 0174-304X. April 14, 2015 published online May 12, 2015 172 Sleep and Epilepsy Syndromes Schmitt

are referred to cited reviews, where they will also find the last for more than 30 minutes and often up to many hours, pioneering literature not cited in this review. constituting autonomic status epilepticus and often misdiag- nosed as .10 Full recovery after a few hours of sleep West Syndrome is reassuring and can allow the physician to avoid unnecessary West syndrome is characterized by infantile spasms and investigation. -like manifestations are common and hypsarrhythmia and usually manifests between 3 and occur without triggers while standing, sitting, or lying down; 12 months of age, although earlier or later onsets are not they may occur with or without other autonomic symptoms. uncommon. The spasms are brief, synchronous, flexor or The affected children are floppy and unresponsive for minutes extensor movements of head, trunk and limbs and typically (up to an hour). Stimulation is ineffective, and recovery is occur in clusters. The infant often—but not always—utters a spontaneous and rapid without residual symptoms.12 brief stereotyped cry immediately after each spasm. Some- Interictal EEG shows a great variability with multifocal times the spasms are subtle, with series of discrete focal jerks high-amplitude spikes often shifting from one region to or tonic contractions, facial grimacing, or transient eye devi- another in sequential EEGs of the same child.10 Occipital ations. Seizures most commonly occur shortly after awaken- spikes are the most common (76%), followed by temporal ing, when EEG shows a “relative normalization.”2 Thus, it is (24%), parietal (16%), central (14%), and frontal (10%) loca- useful to continue the video-EEG recording for several mi- tions alone or in various combinations.11 Sometimes the nutes beyond awakening, particularly when the diagnosis is occipital spikes are “fixation off sensitive” and sleep accen- uncertain or seizures symptoms subtle. Hypsarrhythmia is tuates ISWs.13 Brief generalized discharges of slow waves the pathognomonic EEG feature and is usually apparent intermixed with small spikes are occasionally recorded. awake and asleep but sometimes only appears in sleep.3 About 10% of patients have a normal wake EEG. Themostrelevantprognosticfactoristheetiology,butWest Ictal EEG appears before clinical symptoms. The ictal syndrome itself may significantly contribute to the developmen- discharges are variable and may start posterior or anterior, tal outcome. Treatment delay for more than 3 weeks has been unilaterally or bilaterally, usually with theta waves inter- shown to have a negative impact on later development.4 Earlier mixed with small spikes and fast rhythms, spreading to other studies have indicated that lacking sleep patterns and the brain regions. Autonomic manifestations are not related to a severity of hypsarrhythmia have significant prognostic implica- specificEEGregion.14 tions.5,6 In a recent study, we have shown that hypsarrhythmia, Prognosis is excellent. Most patients (75%) have a single or similar to ESES/CSWS, impairs the physiological overnight de- less than five seizures until remission.11 However, others may crease of slow waves in non-rapid eye movement (NREM) sleep.7 have frequent and prolonged seizures, which are sometimes Moreover, patients with hypsarrhythmia exhibited steeper slow resistant to treatment. Antiepileptic treatment is not recom- waves than healthy infants. Slow waves are a marker for synaptic mended for children with one or brief seizures. Recurrent strength, and the overnight reduction of the slow waves is a seizures are often treated with and valproic marker for downscaling this strength, which in turn is a part of acid.Rectaldiazepamforhomeadministrationshouldbepre- the restorative function of sleep and memory consolidation (see scribed for prolonged seizures. Remission usually occurs within the article by Anne-Laure and Huber, Methods in pediatric sleep 1to2yearsofonset.10 After clinical remission, spikes may persist research and sleep medicine, current issue ). for many years. Neuropsychological testing is usually normal.11 Treatment should start as soon as possible and the effect should be monitored at short intervals by sleep EEG record- Benign Epilepsy with Centrotemporal Spikes ings. According to the recommendations in United Kingdom,8 Benign epilepsy with centrotemporal spike (BECTS), also United States of America,9 and Germany (www.awmf.org/ known as benign , is the most frequent leitlinien/detail/ll/022-022.html), the most effective drugs .15 The onset is between 3 and 13 years are adrenocorticotropic hormone, high doses of oral steroids with remission before the age of 16 years.16 Seizure semiolo- (prednisolone), and . gy is characterized by hemifacial cloni and lateral tonic deviation of the mouth and tongue with salivary flow. Seizure Panayiotopoulos Syndrome symptoms are sometimes preceded by paresthesia involving Panayiotopoulos syndrome is a benign age-related focal epi- cheek, tongue, and lips.17 During the seizure, contact is often lepsy with onset between age 1 and 14 years (76% age 3–6 preserved, the child is able to understand but unable to speak, years).10 Most seizures (70%) occur while the child is asleep, and the next day the children often remember the nocturnal 17% during wakefulness, and 13% upon awakening.11 Seizures seizure precisely. The seizures last from less than a minute to often begin with , retching, and (80–90%), two minutes. Spreading to the homolateral arm and leg or while consciousness is preserved. Common autonomic symp- secondary generalization might occur. Lerman15 distin- toms are , flushing, , incontinence of urine or guished the following three types of nocturnal seizures: (1) feces, hypersalivation, mydriasis or miosis, thermoregulatory brief hemifacial seizures associated with speech arrest and alterations, and breathing or cardiac irregularities.10 The au- drooling in a conscious state; (2) hemifacial seizures with loss tonomic symptoms are usually followed by loss of conscious- of consciousness, gurgling–grunting noises, and vomiting ness, eye and head deviation, widely open eyes, speech arrest, after the seizure; and (3) generalized tonic–clonic seizures hemifacial , or visual hallucinations. Seizures may (GTCS). Seizure frequency is usually low, and approximately end with hemi- or generalized convulsions. Half of the seizures 70% occur during sleep, mainly short after falling asleep or in

Neuropediatrics Vol. 46 No. 3/2015 Sleep and Epilepsy Syndromes Schmitt 173 the morning short before awakening.18 Treatment (with Epilepsy with continuous spike waves during carbamazepine, valproic acid, , , ox- slow sleep results from the association of various carbazepine, or sulthiame) is only necessary when seizures , partial or generalized, occurring are frequent or disturbing.19 Because the extent of EEG during sleep, and atypical absences when awake. abnormalities does not correlate with the seizure propensity Tonic seizures do not occur. The characteristic EEG and prognosis, EEG is not suitable for treatment decisions. pattern consists of continuous diffuse spike waves Interictal EEG is characterized by high-voltage monomor- during slow-wave sleep, which is noted after onset phic centrotemporal spike waves often diffusing to the adja- of seizures. Duration varies from months to years. cent regions. Spike waves are also found midtemporally, Despite the usually benign evolution of seizures, centroparietally, frontocentrally, centro-occipitally, or multi- prognosis is guarded, because of the appearance of focally. They are unifocal or bifocal and appear singly or in neuropsychological disorders. groups. When bilateral asynchronous, they have different rates and amplitudes. Spike waves may shift from side to side ESES/CSWS is an age-related epileptic encephalopathy in consecutive recordings.18,20 During drowsiness and sleep, with seizure onset between 2 months and 12 years (peak frequency and amplitude increase, with a tendency to shift or 2–4 years).29 During the prodromal stage, seizures are uni- spread from side to side. Background activity and physiologi- lateral clonic or tonic–clonic and typically occur out of sleep. cal sleep pattern are usually normal. During ESES, seizure frequency increases and atonic seizures The typical BECTS has no underlying structural brain (falls), and atypical absences appear and become increasingly abnormalities. Therefore, magnetic resonance imaging difficult to control. The lack of tonic seizures allows differen- (MRI) is not necessary when clinical and EEG features are tiation from Lennox–Gastaut syndrome. typical. Genetic disposition was found by Doose and Baier,21 ESES/CSWS is associated with new cognitive deficits and and recently GRIN2A mutation was detected in some indi- behavioral disturbances regardless of previous cognitive sta- viduals with BECTS.22 Children with BECTS have no neuro- tus and development. The regression is either acute or logical or intellectual impairment. However, behavioral and insidious and usually appears some months after the onset neuropsychological problems have been reported and seem of clinical seizure.30 Intelligence quotient or developmental to correlate with the presence of an intermittent slow wave quotient decrease, and several behavior and cognitive abnor- focus during wakefulness, a high number of spikes in the first malities have been reported.29,31 The exact incidence of each hour of sleep (and during whole night sleep), and multiple abnormality is unknown. Attention deficits and hyperactivity asynchronous bilateral spike–wave foci in the first hour of are frequently reported. Other cognitive deficits are expres- sleep.23 Continuous psychological testing during spike–wave sive language disorders (for receptive language disorder see discharges revealed brief episodes of impaired cognitive LKS), dyscalculia, dyslexia, global dyspraxia, apraxia, hemi- function.24 Prognosis is excellent, and the disturbances neglect, impaired visuo- and temporospatial orientation, tend to have normalized by the long-term follow-up. short-term memory impairment, and deficits in reasoning. Regarding behavioral abnormalities, aggressiveness, deficits The Spectrum of Electrical Status Epilepticus in relatedness and inhibition, encopresis, enuresis, bizarre during Slow Sleep behavior, emotional lability, psychotic behavior, anxiety, phobias, autistic-like behavior, stereotypies, coprophagia, Electrical status epilepticus during slow sleep (ESES) is an EEG compulsive hyperorality, depression, strange corporal per- pattern characterized by near-continuous spike–wave dis- ception, automutilation, insensitivity to pain, echolalia, and charges in slow-wave sleep. The first description was presented echopraxia are listed in the review by Galanopoulou et al by Patry et al25 who found an association of ESES with seizures (2000).31 Motor deficits with ataxia, dystonia, or dyspraxia and cognitive dysfunction. Morikawa et al26 proposed the term may occur and may be unilateral.29 “continuous spike–wave discharges during sleep (CSWS),” since EEG during wakefulness shows focal and multifocal spikes “status epilepticus” implied clinical manifestations. In literature, that are usually more marked during the acute stage. The ESES and CSWS are used more or less interchangeably. Other characteristic feature of ESES/CSWS is a distinct increase of epileptic syndromes characterized by a distinct increase of bilateral high-amplitude 1.5 to 2.5/s slow spike waves as soon spike–waves during sleep are atypical benign partial epilepsy as the patient falls asleep (►Fig. 1A, B). The spike–wave index or pseudo-Lennox syndrome and Landau–Kleffner syndrome (SWI) ranged from 85 to 100% during all-night NREM sleep (LKS). These syndromes are variants of ESES/CSWS, and the stages.25,29 Several methods to determine the SWI have been transitions between them are fluent. Recent genetic data indi- reported (for a review, see Scheltens-de Boer).33 We prefer cate a continuum between BECTS, atypical benign partial epi- the method described by Aeby et al34: the percentage lepsy, ESES/CSWS, and LKS.22,27 of seconds with  1 spike–wave complex during the first 30 minutes of NREM sleep during the first and the last sleep Electrical Status Epilepticus during slow sleep/ cycle. Although the importance of a high SWI during sleep is Continuous Spike–Wave Discharges during Sleep agreed on, cutoff values below 85% are used by other authors. The Commission on Classification and Terminology of the Qualitative parameters such as spike amplitude, morphology, International League against Epilepsy28 gave the following frequency, and distribution during sleep and parameters such definition of ESES/CSWS: as background activity, sleep pattern, and sleep architecture

Neuropediatrics Vol. 46 No. 3/2015 174 Sleep and Epilepsy Syndromes Schmitt

Fig. 1 ESES/CSWS, age 8 years (A) awake: single frontal sharp waves, (B) 10 minutes later asleep: continuous bilateral spike waves in NREM sleep, SWI > 85%. Reprint with permission from Schmitt and Wohlrab.32 CSWS, continuous spike–wave discharges during sleep; ESES, electrical status epilepticus during slow sleep; NREM, non-rapid eye movement; SWI, spike–wave index.

might play an important role in determining the severity and deficits is also unknown. Tassinari et al29 hypothesized an prognosis of ESES/CSWS.33 interference of spike waves with the physiological slow-wave About half of the patients with ESES/CSWS have malfor- activity in NREM sleep, resulting in an impairment of brain mations or cortical lesions.31 In particular, prenatal or peri- recovery during the sleep necessary to regain optimal cogni- natal thalamic injuries are associated with ESES/CSWS.35 tive performance. And indeed, recent data by Bölsterli Recently, GRIN2A mutations have been found in patients et al36,37 have shown that the physiological decrease of with ESES/CSWS, BECTS, and LKS supporting the view of a slow waves during sleep is impaired in patients with ESES/ spectrum disorder with fluent passages between these CSWS, and the decrease is more hampered the higher the SWI entities.22,27 The pathomechanism behind the emergence is. They also found that, in most patients with SWI > 85%, the of ESES/CSWS is largely unknown. Disturbance of the cortico- physiological slow-wave decrease is completely lost. EEG thalamic network and an alteration of the NMDA functional MRI studies during spike waves in slow-wave sleep receptor with respect to the GRIN2A mutation have been showed a specific neuronal network of propagation including discussed.22,27 The mechanism responsible for the cognitive the perisylvian region, insula, and cingulate gyrus.38 This

Neuropediatrics Vol. 46 No. 3/2015 Sleep and Epilepsy Syndromes Schmitt 175 activation was associated with deactivations in the default never occur. The SWI in the nocturnal EEG is often < 85%. The mode network which is prominent in neuropsychological treatment options are similar to those in ESES/CSWS.46,47 The processes and memory consolidation during sleep and might epilepsy outcome is good; most patients remain seizure free. explain the neuropsychological deficits in ESES/CSWS. The language improves after the spike waves have disap- Cognitive functioning may improve when spike waves are peared, but deficits in language and cognition often persist. reduced with AEDs. No controlled clinical trials have been Similar to ESES/CSWS, language and cognitive outcomes seem conducted to establish the efficacy of different AEDs, and to depend on the duration of the active period of the successful treatment is often difficult to achieve. The primary disease.46 goal is to improve neuropsychological functions or to prevent cognitive deterioration. Treatment options are steroids, lev- Juvenile Myoclonus Epilepsy or Janz etiracetam, , , valproic acid, Syndrome sulthiame, immunoglobulins, ketogenic diet, and multiple subpial transections.39 Because recent data indicate that Juvenile myoclonus epilepsy (JME) is characterized by strong the cognitive outcome is associated with the duration of chronodependency and association to sleep. Seizures usually CSWS/ESES,40,41 aggressive treatment including steroids appear within 2 hours of awakening, and sleep deprivation is should be considered. known to be a crucial trigger. Clinical and EEG characteristics The long-term outcome of ESES/CSWS is variable and were established by Janz and Christian48 with the name depends on the etiology, the duration of ESES and the “impulsive petit mal” and later renamed JME. The hallmark treatment response.40,41 The behavioral disturbances resolve of JME is myoclonic jerks without loss of consciousness, soon after the EEG has normalized, whereas cognitive func- repeatedly occurring after awakening. The jerks are sponta- tions improve at a slower pace and for a longer time. neous, brief, bilateral, single or repetitive, arrhythmic, and Nevertheless, permanent cognitive impairments often irregular and often occur in brief clusters. Upper limbs are remain. predominantly affected and may make the patients to drop or throw objects such as coffee cups or mobile phones. Violent Atypical Benign Partial Epilepsy/Pseudo-Lennox myoclonic jerks may involve the lower limbs, causing a Syndrome flexion of the knees and falls. In longer series, myoclonic Aicardi and Chevrie42 reported seven children who satisfied jerks may increase in amplitudes and frequency and pass into the criteria for benign partial epilepsy, but their sleep record- GTCSs. They typically occur in the morning after awakening, ings displayed almost continuous slow spike–wave activity. In particularly when the preceding sleep has been insufficient. addition to focal motor seizures, these patients suffered from But they may also occur after a nap or during intermediate or atypical absences and myoclonic and atonic attacks. Because provoked awakenings at night.49 According to a consensus of the favorable course of the children’s condition, they coined meeting in 2011, the occurrence of myoclonic jerks is an the disease atypical benign partial epilepsy. Doose43 de- obligatory criterion for the diagnosis of JME.50 GTCSs are scribed patients who were similar but with mental deficit almost exclusively of the awakening type, often subsequent to and proposed the term pseudo-Lennox syndrome. Epilepsy a cluster of myoclonic jerks. Provoked by insufficient sleep, onset ranged between age 0.4 and 8.5 years (peak 3.1 years).44 they are intense and the postictal asthenia prolonged.49 EEG features, treatment options, and outcomes are similar to Absence seizures occur with a prevalence of 10 to 38%. ESES/CSWS. Within the spectrum, atypical benign partial They are short and infrequent with partial impairment of epilepsy is probably positioned between rolandic epilepsy consciousness and often detected only in long-term EEG and the ESES/CSWS and LKS continuum. recordings.49 Other seizures are perioral reflex myoclonia (precipitated by reading, speaking, and other neuropsycho- Landau–Kleffner Syndrome logical activation) and praxis-induced seizures.51 Photosen- In 1957, Landau and Kleffner reported five children with sitivity with myoclonic jerks or GTCS are reported acquired receptive aphasia in association with epilepsy and with divergent frequencies,51,52 although photoparoxysmal spike waves in EEG and termed the disease “syndrome of responses in EEG are found in 38% of the patients. acquired aphasia with convulsive disorder in children,”45 Diagnosis is made by careful interview of the patient which was later renamed LKS. The syndrome is characterized focusing on myoclonic jerks after awakening. The EEG shows by (1) acquired aphasia due to auditory agnosia; (2) epilepsy; polyspike waves with three or more spikes followed by slow (3) unilateral or lateralized spike waves, bitemporal or diffuse, waves, 2.5 to 3.5/s spike waves, > 3.5/s spike waves and with increase during NREM sleep; (4) normal brain imaging; classical 3/s spike waves (for review see the study by Serafini and (5) improvement of language when spike waves disap- et al).53 Focal or asymmetric spike waves occur. Background pear.46,47 Additional cognitive and behavioral deficits have activity and sleep pattern are normal. Myoclonic jerks are been reported. The onset is acute or insidious and ranged associated with rapid 5 to 20 polyspikes of increasing ampli- from ages 2 to 8 years. Before onset, children are normal and tude with maxima over the frontal region, followed or have already developed age-appropriate language. Seizures preceded by high-amplitude 3 to 4/s slow waves. Perioral (focal motor seizures with and without secondary generali- reflex myoclonia and praxis-induced seizures coincide with zation, atypical absences) are milder than in ESES/CSWS and generalized spikes and rapid spike waves.51 Normal routine mostly easy to treat. In 20 to 30% of the patients, seizures EEG does not exclude the diagnosis of JME. Long-term video-

Neuropediatrics Vol. 46 No. 3/2015 176 Sleep and Epilepsy Syndromes Schmitt

EEG in sleep or nocturnal sleep deprivation followed by a quirement, and a high relapse rate after AED withdrawal. short morning nap and subsequent sudden awakening might Even the long-term outcome is in line with the prognosis of be helpful. Because sleep deprivation bears the risk of GTCS, JME.59 0.5 mg/kg clobazam is recommended as soon as myoclonic 52 jerks have been recorded. Nocturnal Frontal Lobe Epilepsy JME begins between 8 and 26 years of age (peak, 12–18 years) with a female predominance.52 JME is not associated Nocturnal frontal lobe epilepsy (NFLE) manifests at any age with neurological or mental deterioration, but several but most commonly in childhood (mean, 14 Æ 10 years).60 studies suggest psychiatric comorbidity and specificcogni- The diagnosis is sometimes difficult, and symptoms are often tive deficits. Schmitz et al54 summarized the deficits as mistaken for parasomnia or other nonepileptic sleep disor- problems in cognitive tasks linked to the frontal lobes ders. In a clinical and polygraphical overview of 100 conse- with impact on interpersonal relationships and social cutive cases, Provini et al61 distinguished the following three outcome. However, the majority of patients with JME subtypes of NFLE: have no relevant neuropsychological deficits or psychiatric • Paroxysmal arousal (range, 2–20 seconds): Patients sud- comorbidity. denly open their eyes, raise their heads, or sit up in bed JME is treatable in most patients.55 Valproic acid (1,000– with a bizarre dystonic posture of the limbs, show bending 2,000 mg/d) is very effective but is not the first-line treat- or rocking movements, stare around with a frightened or ment in females of child-bearing age or in obese patients. surprised expression, and sometimes scream. After the is also efficacious but less tolerated and some- attack, patients quickly go back to sleep. times associated with cognitive adverse effects. • Nocturnal paroxysmal dystonia (20 seconds–2 minutes): is effective but may aggravate myoclonic jerks. Levetiracetam Nocturnal paroxysmal dystonia begins with a paroxysmal is not mentioned for JME in an “Updated ILAE evidence arousal, followed by wide, often violent motor attacks with review of antiepileptic drug efficacy”19 but seems to be complex dystonic–dyskinetic features. Attacks may show another option. Carbamazepine, , gabapentin, the typical pattern of supplementary motor seizures with , , und vigabatrine may precipitate or extension of the ipsilateral limb, flexion of the contralat- aggravate absence seizures, myoclonic seizures, and eral limb, and rotation of the head. Other attacks display GTCS.19 A lifestyle with regular wake–sleep rhythm is rec- rhythmic or ballistic movements with kicking, cycling, or ommended, and patients should know about the risk of body rocking. seizure recurrence after sleep deprivation and excessive • Episodic nocturnal wanderings (range, 1–3 minutes) are alcohol intake. Because in adolescence regimentations are characterized by stereotypic, agitated ambulation with often difficult to enforce and because excessive regimenta- suddenly changing directions, jumping, and screaming. tion may be counterproductive for normal socialization, the perils of seizures (e.g., drowning in bath, driving) should be Intraindividual seizures are remarkably stereotypical, al- expressly communicated. though all three NFLE types are sometimes present in the Lifelong treatment is recommended in most studies. A same patient. Almost all seizures occur during NREM sleep, recent retrospective cohort study in 66 patients with JME two-thirds in stage 1 to stage 2 and one-third in stage 3 to and follow-up of 44 years (range, 20–69 years) revealed 11 stage 4. Seizure frequency is at mean 20 Æ 11 seizures per (28%) patients who were off medication for at least 5 years. months and 1 to 20 (mean 3 Æ 3) per night. Nocturnal Additional absence seizures at onset of JME seems to be a secondary generalized seizures with prolonged tonic/vibra- predictor of an unfavorable outcome regarding seizure tory and asymmetric features occur and seizures during the freedom.56 day similar to those during sleep are occasionally reported. The majority of the patients are not aware of their nocturnal Grand Mal Seizures on Awakening motor behavior. Carbamazepine is reported to be effective, but approximately 50% of the patients are drug refractory. Grand mal seizures on awakening (GMA) is both a separate There is no spontaneous remission and always a relapse when entity and part of other generalized epilepsies. Similar to AEDs are withdrawn.61 JME, GMA have strong chronodependency and occur after Interictal EEG is normal or may show focal epileptic awakening or in the late afternoon or evening hours of leisure abnormalities awake or asleep. Ictal video-EEG depicts dif- and relaxation.57 In juvenile absence epilepsy, GMA may fuse or focal flattening of the background activity, focal theta precede the manifestation of absence seizures,16 and in JME or delta activity, and sometimes spike waves over the frontal, GMA is often the reason to seek medical attention. Age of frontotemporal, vertex, or temporal region. However, in half onsetofpureGMAis6to35years.57 Although GMA is of the registered seizures, EEG fails to disclose an ictal recognized as a distinct nosological entity by the Interna- pattern.61 tional League Against Epilepsy,16 the debate is ongoing NFLE with autosomal dominant transmission (ADNFLE) whether GMA is an entity separate from JME.58 Both syn- was first described by Scheffer et al.62 Meanwhile, several dromes have similar profiles, with seizures provoked by mutations, both in coding for subunits of the nicotinic ace- sleep deprivation, occurrence after awakening, comparable tylcholine receptor (CHRNA4) and in other genes (KCNT1 and EEG changes, response to similar AED, long treatment re- DEPDC5) have been found.63,64

Neuropediatrics Vol. 46 No. 3/2015 Sleep and Epilepsy Syndromes Schmitt 177

A vague relation between NFLE and parasomnia has been during nap (natural sleep or drug induced), during night, or discussed and reasoned by a high family history of parasomnias after sleep deprivation. EEG in natural sleep is recommended in patients with NFLE and by anamnestic episodes of parasomnia in infants and easy to perform when the time schedule is in patients who subsequently develop NFLE.61 Distinguishing carefully planned. Drug-induced nap EEGs are an option for NFE from nonepileptic parasomnias is sometimes difficult. The patients with suspected epilepsy and nonconclusive wake EEG may be nondiagnostic, but key features of NFLE and para- EEG and for children with evidence of ESES/CSWS or LKS. somnia are helpful for differentiation60: Overnight EEG recordings should be performed when nap EEG is suspicious for ESES/CSWS or when frontal lobe epilep- • NFLE seizures are frequent (> 20/month;  3/night), sy is suspected (video-EEG). Deprivation of sleep seems to be NREM parasomnias are less frequent (< 14/month, 1–2/ an independent activator of spike waves but is accompanied night). by a significant burden for patient and parents and bears the • NFLE often lasts < 2 minutes and parasomnias seconds to risk of an unintended seizure provocation. We use sleep 30 minutes. deprivation very rarely, almost always in a hospital setting • Movements are stereotyped and vigorous in NFLE and not and only when JME is suspected or a patient’s history and EEG highly stereotyped in parasomnias. are not conclusive. • Extrapyramidal symptoms, stiffening, dystonic posturing, The periods before falling asleep and after awakening may or bipedal automatisms occur in NFLE but is very unusual also contain useful information. EEG recordings after awak- in parasomnias. ening are particularly recommended in patients with West • NFLE arise during stage 2 NREM sleep, parasomnias arise syndrome (registration of infantile spasms) and JME (regis- from slow-wave sleep. tration of generalized spike waves or myoclonic jerks). • Recall of nocturnal events favors NFLE whereas absence of recollection is nondiagnostic.

Home videos and the application of “The Frontal Lobe Epilepsy and Parasomnias (FLEP)” scale may be helpful in References differentiation, and video-EEG polysomnography is recom- 1 Dinner DS, Lüders HO. Relationship of epilepsy and sleep: over- view. In: Dinner DS, Lüders HO, eds. Epilepsy and sleep. Physio- mended when differentiation is not possible by history.60 logical and Clinical Relationships. San Diego, CA: Academic Press; 2001:2–18 Influence of Sleep on Other Epilepsy 2 Shewmon DW. Ictal aspects with emphasis on unusual variants. In: Dulac O, Chugani HT, Dalla Bernardina B, eds. Infantile Spasms Syndromes and West Syndrome. London: WB Saunders Company; 1994: – Absence epilepsies: Absence epilepsies are characterized by 36 51 3 Watanabe K, Negoro T, Aso K, Matsumoto A. Reappraisal of absence seizures and generalized 3/s spike waves. Seizures interictal electroencephalograms in infantile spasms. Epilepsia are only detectable when awake, but ISWs are most distinct in 1993;34(4):679–685 the first sleep cycle. During sleep, the ISW bursts become 4 O’Callaghan FJ, Lux AL, Darke K, et al. The effect of lead time to shorter and irregular and are intermixed with polyspikes, and treatment and of age of onset on developmental outcome at 4 years focal spike waves may appear in the frontal regions. in infantile spasms: evidence from the United Kingdom Infantile – Lennox–Gastaut syndrome: Lennox–Gastaut syndrome is Spasms Study. Epilepsia 2011;52(7):1359 1364 5 Rating D, Seidel U, Grimm B, Hanefeld F. The prognostic value of characterized by tonic, tonic–clonic, myoclonic, and atypical EEG patterns in epilepsies with infantile spasms. Brain Dev 1987; absence seizures. Seizures are drug refractory and the patients 9(4):361–364 mentally disabled. Tonic axial seizures frequently occur in 6 Kramer U, Sue WC, Mikati MA. Hypsarrhythmia: frequency of sleep, although they are often subtle and detectable only in variant patterns and correlation with etiology and outcome. video-EEG recordings. Ictal EEG shows diffuse fast 10 to 20/s Neurology 1997;48(1):197–203 activity often preceded by attenuation of the background 7 Fattinger S, Schmitt B, Bölsterli Heinzle BK, Critelli H, Jenni OG, Huber R. Impaired slow wave sleep downscaling in patients activity. The ictal discharges are usually brief and often with infantile spasms. Eur J Paediatr Neurol 2015;19(2): without visible symptoms. Interictal EEG is characterized by 134–142 generalized slow spike-wave complexes which increase dur- 8 Hancock EC, Osborne JP, Edwards SW. Treatment of infantile ing NREM sleep. spasms. Cochrane Database Syst Rev 2013;6:CD001770 : Although in most patients seizures 9 Go CY, Mackay MT, Weiss SK, et al; Child Neurology Society; American Academy of Neurology; Report of the Guideline Devel- occur predominantly during wakefulness, ISW activity in- opment Subcommittee of the American Academy of Neurology creases in frequency and extent during NREM sleep with and the Practice Committee of the Child Neurology Society. maximum in stages 3 and 4. Evidence-based guideline update: medical treatment of infantile spasms. Neurology 2012;78(24):1974–1980 10 Panayiotopoulos CP, Michael M, Sanders S, Valeta T, Koutrouma- Sleep and Sleep Deprivation in the nidis M. Benign childhood focal epilepsies: assessment of estab- Diagnostic of Epilepsy lished and newly recognized syndromes. Brain 2008;131(Pt 9): 2264–2286 Sleep EEG recordings may be helpful in patients with sus- 11 Specchio N, Trivisano M, Di Ciommo V, et al. Panayiotopoulos pected epilepsy and nonconclusive awake EEG. Depending on syndrome: a clinical, EEG, and neuropsychological study the clinical question, sleep recordings can be performed of 93 consecutive patients. Epilepsia 2010;51(10):2098–2107

Neuropediatrics Vol. 46 No. 3/2015 178 Sleep and Epilepsy Syndromes Schmitt

12 Koutroumanidis M, Ferrie CD, Valeta T, Sanders S, Michael M, 31 Galanopoulou AS, Bojko A, Lado F, Moshé SL. The spectrum of Panayiotopoulos CP. Syncope-like epileptic seizures in Panayioto- neuropsychiatric abnormalities associated with electrical status poulos syndrome. Neurology 2012;79(5):463–467 epilepticus in sleep. Brain Dev 2000;22(5):279–295 13 Caraballo R, Cersósimo R, Fejerman N. Panayiotopoulos syndrome: 32 Schmitt B, Wohlrab G. EEG in der Neuropädiatrie. Berlin Heidel- a prospective study of 192 patients. Epilepsia 2007;48(6): berg: Springer-Verlag; 2013 1054–1061 33 Scheltens-de Boer M. Guidelines for EEG in encephalopathy relat- 14 Specchio N, Trivisano M, Claps D, Battaglia D, Fusco L, Vigevano F. ed to ESES/CSWS in children. Epilepsia 2009;50(Suppl 7):13–17 Documentation of autonomic seizures and autonomic status 34 Aeby A, Poznanski N, Verheulpen D, Wetzburger C, Van Bogaert P. epilepticus with ictal EEG in Panayiotopoulos syndrome. Epilepsy Levetiracetam efficacy in epileptic syndromes with continuous Behav 2010;19(3):383–393 spikes and waves during slow sleep: experience in 12 cases. 15 Lerman P. Benign partial epilepsy with centro-temporal spikes. In: Epilepsia 2005;46(12):1937–1942 Roger J, Dravet C, Bureau M, Dreifuss FE, Wolf P, eds. Epileptic 35 Guzzetta F, Battaglia D, Veredice C, et al. Early thalamic injury Syndromes in Infancy, Childhood and Adolescence. London and associated with epilepsy and continuous spike-wave during slow Paris: John Libbey Eurotext Ltd; 1985:150–158 sleep. Epilepsia 2005;46(6):889–900 16 Commission on Classification and Terminology of the Internation- 36 Bölsterli BK, Schmitt B, Bast T, et al. Impaired slow wave sleep al League Against Epilepsy. Proposal for classification of epilepsies downscaling in encephalopathy with status epilepticus during and epileptic syndromes. Epilepsia 1985;26(3):268–278 sleep (ESES). Clin Neurophysiol 2011;122(9):1779–1787 17 Loiseau P, Beaussart M. The seizures of benign childhood epilepsy 37 Bölsterli Heinzle BK, Fattinger S, Kurth S, et al. Spike wave location with Rolandic paroxysmal discharges. Epilepsia 1973;14(4): and density disturb sleep slow waves in patients with CSWS 381–389 (continuous spike waves during sleep). Epilepsia 2014;55(4): 18 Eeg-Olofsson O. Rolandic epilepsy. In: Bazil CW, Malow BA, 584–591 Sammaritano MR, eds. Sleep and Epilepsy: The Clinical Spectrum. 38 Siniatchkin M, Groening K, Moehring J, et al. Neuronal networks in Amsterdam: Elsevier; 2002:257–263 children with continuous spikes and waves during slow sleep. 19 Glauser T, Ben-Menachem E, Bourgeois B, et al; ILAE Subcommis- Brain 2010;133(9):2798–2813 sion on AED Guidelines. Updated ILAE evidence review of antiepi- 39 Veggiotti P, Pera MC, Teutonico F, Brazzo D, Balottin U, Tassinari leptic drug efficacy and effectiveness as initial monotherapy for CA. Therapy of encephalopathy with status epilepticus during epileptic seizures and syndromes. Epilepsia 2013;54(3):551–563 sleep (ESES/CSWS syndrome): an update. Epileptic Disord 2012; 20 Lerman P, Kivity S. Benign focal epilepsy of childhood. A follow-up 14(1):1–11 study of 100 recovered patients. Arch Neurol 1975;32(4):261–264 40 Pera MC, Brazzo D, Altieri N, Balottin U, Veggiotti P. Long-term 21 Doose H, Baier WK. Benign partial epilepsy and related conditions: evolution of neuropsychological competences in encephalopathy multifactorial pathogenesis with hereditary impairment of brain with status epilepticus during sleep: a variable prognosis. Epi- maturation. Eur J Pediatr 1989;149(3):152–158 lepsia 2013;54(Suppl 7):77–85 22 Lemke JR, Lal D, Reinthaler EM, et al. Mutations in GRIN2A cause 41 Seegmüller C, Deonna T, Dubois CM, et al. Long-term outcome idiopathic focal epilepsy with rolandic spikes. Nat Genet 2013; after cognitive and behavioral regression in nonlesional epilepsy 45(9):1067–1072 with continuous spike-waves during slow-wave sleep. Epilepsia 23 Nicolai J, van der Linden I, Arends JB, et al. EEG characteristics 2012;53(6):1067–1076 related to educational impairments in children with benign 42 Aicardi J, Chevrie JJ. Atypical benign partial epilepsy of childhood. childhood epilepsy with centrotemporal spikes. Epilepsia 2007; Dev Med Child Neurol 1982;24(3):281–292 48(11):2093–2100 43 Doose H. Symptomatology in children with focal sharp waves of 24 Binnie CD. Significance and management of transitory cognitive genetic origin. Eur J Pediatr 1989;149(3):210–215 impairment due to subclinical EEG discharges in children. Brain 44 Hahn A. Atypical benign partial epilepsy/pseudo-Lennox syn- Dev 1993;15(1):23–30 drome. Epileptic Disord 2000;2(Suppl 1):S11–S17 25 Patry G, Lyagoubi S, Tassinari CA. Subclinical “electrical status 45 Landau WM, Kleffner FR. Syndrome of acquired aphasia with epilepticus” induced by sleep in children. A clinical and electro- convulsive disorder in children. Neurology 1957;7(8):523–530 encephalographic study of six cases. Arch Neurol 1971;24(3): 46 Caraballo RH, Cejas N, Chamorro N, Kaltenmeier MC, Fortini S, 242–252 Soprano AM. Landau-Kleffner syndrome: a study of 29 patients. 26 Morikawa T, Seino M, Osawa T, Yagi K. Five children with continu- Seizure 2014;23(2):98–104 ous spike-wave discharges during sleep. In: Roger J, Dravet C, 47 Deonna TW. Acquired epileptiform aphasia in children (Landau- Bureau M, Dreifuss FE, Wolf P, eds. Epileptic Syndromes in Infancy, Kleffner syndrome). J Clin Neurophysiol 1991;8(3):288–298 Childhood and Adolescence. London and Paris: John Libbey Euro- 48 Janz D, Christian W. Impulsiv-Petit mal. Dtsch Z Nervenheilkd text Ltd; 1985:205–212 1957;176(3):346–386 27 Carvill GL, Regan BM, Yendle SC, et al. GRIN2A mutations cause 49 Genton P, Thomas P, Kasteleijn-Nolst Trenité DG, Medina MT, epilepsy-aphasia spectrum disorders. Nat Genet 2013;45(9): Salas-Puig J. Clinical aspects of juvenile myoclonic epilepsy. Epi- 1073–1076 lepsy Behav 2013;28(Suppl 1):S8–S14 28 Commission on Classification and Terminology of the International 50 Kasteleijn-Nolst Trenité DG, Schmitz B, Janz D, et al. Consensus on League Against Epilepsy. Proposal for revised classification of diagnosis and management of JME: From founder’s observations epilepsies and epileptic syndromes. Epilepsia 1989;30(4):389–399 to current trends. Epilepsy Behav 2013;28(Suppl 1):S87–S90 29 Tassinari CA, Rubboli G, Volpi L, Billard C, Bureau M. Electrical 51 Mayer TA, Schroeder F, May TW, Wolf PT. Perioral reflex myoclo- status epilepticus during slow sleep (ESES or CSWS) including nias: a controlled study in patients with JME and focal epilepsies. acquired epileptic aphasia (Landau-Kleffner syndrome). In: Roger Epilepsia 2006;47(6):1059–1067 J, Bureau M, Dravet C, Genton P, Tassinari CA, Wolf P, eds. Epileptic 52 Thomas P, Genton P, Gelisse P, Wolf P. Juvenile myoclonic epilepsy. Syndromes in Infancy, Childhood and Adolescence. London and In: Roger J, Bureau M, Dravet C, Genton P, Tassinari CA, Wolf P, eds. Paris: John Libbey Eurotext Ltd; 2005:295–314 Epileptic Syndromes in Infancy, Childhood and Adolescence. 30 Roulet Perez E, Davidoff V, Despland PA, Deonna T. Mental and London and Paris: John Libbey Eurotext Ltd; 2005:367–388 behavioural deterioration of children with epilepsy and CSWS: 53 Serafini A, Rubboli G, Gigli GL, Koutroumanidis M, Gelisse P. acquired epileptic frontal syndrome. Dev Med Child Neurol 1993; Neurophysiology of juvenile myoclonic epilepsy. Epilepsy Behav 35(8):661–674 2013;28(Suppl 1):S30–S39

Neuropediatrics Vol. 46 No. 3/2015 Sleep and Epilepsy Syndromes Schmitt 179

54 Schmitz B, Yacubian EM, Feucht M, Hermann B, Trimble M. 60 Derry CP. Sleeping in fits and starts: a practical guide to distin- Neuropsychology and behavior in juvenile myoclonic epilepsy. guishing from sleep disorders. Pract Neurol Epilepsy Behav 2013;28(Suppl 1):S72–S73 2014;14(6):391–398 55 Crespel A, Gelisse P,Reed RC, et al. Management of juvenile myoclonic 61 Provini F, Plazzi G, Tinuper P, Vandi S, Lugaresi E, Montagna P. epilepsy. Epilepsy Behav 2013;28(Suppl 1):S81–S86 Nocturnal frontal lobe epilepsy. A clinical and polygraphic 56 Senf P, Schmitz B, Holtkamp M, Janz D. Prognosis of juvenile overview of 100 consecutive cases. Brain 1999;122(Pt 6): myoclonic epilepsy 45 years after onset: seizure outcome and 1017–1031 predictors. Neurology 2013;81(24):2128–2133 62 Scheffer IE, Bhatia KP, Lopes-Cendes I, et al. Autosomal dominant 57 Janz D. Epilepsy with grand mal on awakening and sleep-waking nocturnal frontal lobe epilepsy. A distinctive clinical disorder. cycle. Clin Neurophysiol 2000;111(Suppl 2):S103–S110 Brain 1995;118(Pt 1):61–73 58 Genton P, Gonzales Sanchez M, Thomas P. Epilepsy with Grand Mal on 63 Heron SE, Smith KR, Bahlo M, et al. Missense mutations in the awakening. In: Roger J, Bureau M, Dravet C, Genton P, Tassinari CA, sodium-gated potassium channel gene KCNT1 cause severe auto- Wolf P, eds. Epileptic Syndromes in Infancy, Childhood and Adoles- somal dominant nocturnal frontal lobe epilepsy. Nat Genet 2012; cence. London and Paris: John Libbey Eurotext Ltd; 2005:389–394 44(11):1188–1190 59 Holtkamp M, Kowski AB, Merkle H, Janz D. Long-term outcome in 64 Picard F, Makrythanasis P, Navarro V, et al. DEPDC5 mutations in epilepsy with grand mal on awakening: forty years of follow-up. families presenting as autosomal dominant nocturnal frontal lobe Ann Neurol 2014;75(2):298–302 epilepsy. Neurology 2014;82(23):2101–2106

Neuropediatrics Vol. 46 No. 3/2015